DALLAS-"Interim results of a
phase III trial of gemcitabine (Gemzar)
plus paclitaxel compared with paclitaxel
alone in anthracycline-pretreated metastatic
breast cancer patients show statistically
significant improvements in time to
progression and objective response rate
due to the addition of gemcitabine to
paclitaxel," Joyce O'Shaughnessy, MD, reported
(ASCO abstract 25).
"There was a trend to improved pain
scores, reduced analgesic use, and increases
in overall quality of life in the combination
of gemcitabine plus paclitaxel, which
was well tolerated with manageable toxicity.
Because of the favorable risk-benefit
profile reported in this controlled clinical
trial, gemcitabine plus paclitaxel is a new
treatment option for metastatic breast cancer
patients who may benefit from combination
chemotherapy," she continued. Dr.
O'Shaughnessy is co-director of breast
cancer research at Baylor-Sammons Cancer
Center and US Oncology, Dallas.
"We enrolled only patients who had
not been treated with chemotherapy for
metastatic disease, but had received anthracycline-
based chemotherapy as adjuvant
or neoadjuvant therapy, or a nonanthracycline-
based adjuvant regimen if
anthracyclines were contraindicated," she
said. "Prior hormonal therapy was permitted.
Patients had at least one site of
bidimensionally measurable disease."
Other eligibility criteria included unresectable,
locally recurrent, or metastatic
breast cancer and Karnofsky performance
status of at least 70.
98 Centers Participate
Patients at 98 participating centers in
19 countries were randomized to receive
gemcitabine/paclitaxel or paclitaxel alone.
The doses of gemcitabine/paclitaxel were
chosen based on phase I and II data that
had shown acceptable safety and promising
antitumor activity. Standard gemcitabine
premedications were utilized on
both study arms.
Patients were randomized to receive
either:

paclitaxel 175 mg/m2 given over
3 hours followed by gemcitabine 1,250
mg/m2 on day 1, and then gemcitabine
again, 1,250 mg/m2 on day 8;

paclitaxel alone at 175 mg/m2 over
3 hours.

Both regimens were given every 21
days.
There were 257 patients in each treatment
group, well-matched for age and
ethnicity and 97% of patients had metastatic
breast cancer at study entry.
This was a patient population with a
relatively significant tumor burden with
73% of patients on both arms of the study
having visceral metastases. On the combined
arm, 43% of patients had three or
more sites of metastatic disease, compared
with 41% on the paclitaxel-alone arm.
Ninety-seven percent of the gemcitabine/
paclitaxel patients and 96% of the paclitaxel
patients had been previously treated
with an anthracycline-based adjuvant chemotherapy.
Hormone receptor status was
well balanced on the two arms of the
study. Approximately 50% of patients on
both study arms were previously treated
with a hormonal agent.
All sites of disease were assessed every
8 weeks and treatment was continued until
documented disease progression.
Longer Time to Progression
The interim analysis was conducted
when at least 400 patients had developed
progressive disease and provided 75%
power to detect a hazard ratio of 0.75 for
time to progression with a two-sided significance
level of 0.028. The primary objective
for the final analysis, which will be
conducted in late 2004, is overall survival.
The study sample size provides 80% power
to detect a hazard ratio for overall survival
of 0.75, with a two-sided significance
level of 0.03.
The median delivered dose of gemcitabine
was 1,134 mg/m2, which was 85% of
the intended dose. Patients on both arms
of the study received a median delivered
dose of paclitaxel of 175 mg/m2. Only a
small minority of intended gemcitabine
doses were omitted or reduced.
With 424 events having occurred at
the time of the interim analysis, the median
time-to-progression with combined
gemcitabine/paclitaxel was 5.4 months
compared with 3.5 months with paclitaxel
alone. At 6 months, 44% of the gemcitabine/
paclitaxel patients were progression-
free, compared with 30% of paclitaxel
patients. The hazard ratio for progression
with gemcitabine/paclitaxel vs paclitaxel
alone was 0.73, which was statistically significant
with a two-sided P value of .0013.
The objective rate with gemcitabine/paclitaxel
was 39.3% compared with 25.6%
for paclitaxel and the difference between
these two was statistically significant.
The median duration of response was
8.8 months with gemcitabine/paclitaxel
compared with 7.2 months with paclitaxel,
a nonsignificant difference.
Pain Improvement
An analysis by cycle of mean brief pain
inventory scores for symptomatic patients
revealed a nonsignificant trend toward
pain improvement over time with gemcitabine/
paclitaxel compared with paclitaxel
alone. This improvement in pain
scores was associated with a decreased
analgesic requirement in 25% of patients,
compared with 15% of patients on the
paclitaxel alone arm. In cycles five and six,
patients on the gemcitabine/paclitaxel arm
had a statistically significant improvement
in their quality of life, compared with
their own baseline scores showing no adverse
effect of the combination on this
measure of quality of life.
Mild Toxicities
Grade 3/4 hematologic toxicities and
transfusions were relatively mild on both
study arms. Of patients treated with gemcitabine/
paclitaxel, 17% developed grade 4 neutropenia compared with 7% with
paclitaxel alone. Of the gemcitabine/paclitaxel
treated patients, 5% developed
grade 3 thrombocytopenia. Febrile neutropenia
or sepsis was observed in 5% of
gemcitabine/paclitaxel treated patients
compared with 2% of paclitaxel patients.
Red blood cell transfusions were administered
to 10% of the gemcitabine/paclitaxel-
treated patients compared with 4%
of paclitaxel alone) patients, although
grade 3/4 anemia was uncommon. For
grade 3/4 nonhematologic toxicity, there
were modest differences in the incidence
of fatigue as well as asymptomatic increases
in hepatic transaminases in the
gemcitabine/paclitaxel arm of the study.
At this interim analysis, the percent of
patients who died on study or during the
30-day follow-up period was similar on
the two arms, as was the incidence of
drug-related deaths, which was one patient
on each arm. Of patients treated
with gemcitabine/paclitaxel, 6% discontinued
therapy due to drug-related adverse
events compared with 2% with paclitaxel
alone.

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